All publications herein are incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. The following description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
Inflammatory bowel disease (IBD) includes several forms of inflammatory diseases and conditions affecting various parts of the gastrointestinal (GI) tract, such as the colon and small intestine. The main forms of IBD include Crohn's disease (CD) and ulcerative colitis (UC), among other forms of colitis. Hallmarks of IBD include inflammation of the digestive tract in compartments of the epithelial mucosa or transmural lesions in the bowel wall. The inflammatory state of the GI tract in CD and others forms of IBD are due in part to an autoimmune response, and a particularly serious complication is fibrosis (also known as fibrostenosis), wherein excessive connective tissue is generated as a result of chronic inflammation of intestinal tissue.
For example, CD is a chronic inflammatory disease that can affect any part of the gastrointestinal tract. The incidence of CD is increasing, with an incidence of between 3.1 and 14.6 cases per 100,000 person-years and an overall prevalence between 26.0 and 198.5 cases per 100,000 person years. The mean age at diagnosis of CD is generally in the third decade of life with similar frequency in men and women. This disease has a chronic intermittent course with only 10% of patients experiencing prolonged remission. Therapy for this disorder has progressed from non-specific agents such as glucocorticoids and 5-aminosalicylate compounds to biologic agents that target specific aspects of the immune response such as inhibitors of TNF-α. An improved understanding of the immune defects in CD will improve the spectrum of available therapy.
As TNF-α is well-known to be a pro-inflammatory cytokine, targeting biological factors related to the TNF-α signaling pathway may lead to diminution of the causative agents which promote IBD pathogenesis. As a leading example, TL1A (TNFSF15) is a member of the TNF superfamily that binds to death domain receptor 3 (DR3, TNFRSF25) (FIG. 1A). The expression of TL1A is increased in inflamed tissue of colon and small bowel of CD patients, co-localizing to macrophages and T-cells. In particular, lamina propria of the epithelial mucosa and peripheral CD4+CCR9+ T-cells constitutively express membrane TL1A and are especially sensitive to TL1A stimulation. The role of TL1A in the pathology of mucosal inflammation has been recently tested by using neutralizing antibodies to TL1A where inactivating the function of TL1A can attenuate inflammation in various murine colitis models. Together, TL1A/DR3 signaling could have a pleiotropic effect and include amplifying the innate immune response, modulating adaptive immunity by augmenting Th1, Th2, and Th17 effector cell function, and T-cell accumulation and immunopathology of inflamed tissue. Given its immune modulatory effects, blocking TL1A-DR3 signaling is a promising therapeutic strategy in a variety of T-cell-dependent autoimmune diseases including forms of IBD, such as CD and UC, and related fibrotic conditions such as liver periportal fibrosis, bile duct fibrosis, primary biliary cirrhosis, livery periportal inflammation and bile duct inflammation.